Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen.
The T cell receptor (TCR) inherently has dual specificity. T cells must recognize self-antigens in the thymus during maturation and then discriminate between foreign pathogens in the periphery. A molecular basis for this cross-reactivity is elucidated by the crystal structure of the alloreactive 2C TCR bound to self peptide-major histocompatibility complex (pMHC) antigen H-2Kb-dEV8 refined against anisotropic 3.0 angstrom resolution x-ray data. The interface between peptide and TCR exhibits extremely poor shape complementarity, and the TCR beta chain complementarity-determining region 3 (CDR3) has minimal interaction with the dEV8 peptide. Large conformational changes in three of the TCR CDR loops are induced upon binding, providing a mechanism of structural plasticity to accommodate a variety of different peptide antigens. Extensive TCR interaction with the pMHC alpha helices suggests a generalized orientation that is mediated by the Valpha domain of the TCR and rationalizes how TCRs can effectively "scan" different peptides bound within a large, low-affinity MHC structural framework for those that provide the slight additional kinetic stabilization required for signaling.
Garcia
K C
KC
Department of Molecular Biology and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Degano
M
M
Pease
L R
LR
Huang
M
M
Peterson
P A
PA
Teyton
L
L
Wilson
I A
IA
D000818:Animals; D003460:Crystallization; D018360:Crystallography, X-Ray; D006183:H-2 Antigens / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D009842:Oligopeptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins